Our initial focus was on MCD, a syndrome in which infected B cells are in the lytic phase of the viral replication cycle. Infected cells express several KSHV structural glycoproteins at the surface, including gH/gL, gB, and K8.1A. Though a relatively rare disease, MCD incidence continues to rise despite antiretroviral therapy and the associated improvements in immune function. MCD if a life-threatening disease (median life expectancy <3 years after diagnosis), and no standards for clinical management have been developed. Hence immunotoxins to selectively kill infected B cells may prove beneficial. We previously reported the design and characterization of an immunotoxin, YC15-PE38, that potently killed a gH transfectant cell line and strongly inhibited infectious virus production from Vero-219 cells harboring an episomal infectious KSHV genome with EGFP and RFP that serve as reporters for latent and lytic infection, respectively. We have now characterized a new immunotoxin, 2014-PE38, against a the KSHV glycoprotein K8.1A, which is expressed earlier than gH as cells enter the lytic phase of replication. This immunotoxin potently inhibits infectious virus production from Vero-219 cells; control experiments verified the specificity of this effect based on targeting K8.1A surface antigen, and confirmed that the inhibitory effects were due to selective killing of the virus-producing cells. In combination drug treatment experiments, the immunotoxin complemented the activity of ganciclovir. Assays have been extended to other cell types that are more biologically relevant, incuding the iSLK#10, an endothelial cell line that harbors a reporter-carrying KSHV genome inducible by doxycicline, and BCBL cells derived from a primary infusion lymphoma in which KSHV lytic expression can be experimentally induced. Oddly, neither YC15-PE38 or 2014-PE38 were active against the chronically infected BCBL-1 PEL cell line, or other human PEL cell lines tested, based on both direct cell killing assays and measurements of effects on virus release. Whether this represents an unusual feature of PEL-derived cells, or is characteristic of all KSHV-infected B cell types, remains an important unanswered question.